PACAP (pituitary adenylate cyclase activiting polypeptide) is a neuropeptide neurotransmitter released at synapses that transduce stress responses to the brain, and mediate homeostatic adjustments to stress by the organism. Chronic stress is implicated as a causative factor in depression and post-traumatic stress disorder. Understanding the cellular mechanisms of stress transduction is crucial to developing effective therapeutic interventions for stress disorders.nvolved in both detection of, and allostatic responses to, metabolic and psychogenic stressors. Using insulin injection as a systemic stressor we have previously shown that PACAP released at the adrenomedullary synapse is required for prolonged catecholamine release that promotes glucohomeostasis, and survival, during insulin stress. In the past year, we have found that PACAP's actions at this synapse include not only enhanced catecholamine synthesis and release, but increased transcription of genes encoding neuroprotective and steroidogenic factors. These presumably limit cellular damage accompanying overstimulation of stress-transducing cells, and augment production of adrenocortical steroids that mediate long-term adaptation to stress. PACAP contained in and released from neurons in the hypothalamus of the brain is also important in the central nervous system response to psychological stress. Hypothalamic responses leading to pituitary activation following exposure to at least one type of psychogenic stressor is eliminated in PACAP-deficient mice. PACAP's effects on gene activation in both the adrenal gland and the hypothalamus involve the second messenger cyclic AMP, and this signaling may occur via a novel signaling pathway different from the one through which cyclic AMP exerts its effects on memory and learning. We are attempting to characterize this signaling pathway so that pharmacological interventions in stress relevant to mental health might be developed that do not at the same time interfere with normal processes of memory and learning that depend on cyclic AMP. In a related project, we and our colleagues at the University of Rouen in France, and the University of Gronigen in the Netherlands, have shown that neuroprotection actions of the cytokine tumor necrosis factor-alpha (TNF-alpha) mediated through the type 2 TNF receptor may be mediated by the induction of specific, previously uncharacterized genes, expressed in both cerebrocortical neurons and chromaffin cells of the adrenal medulla. Using microarray analysis, in which changes in the levels of activation of all the genes in the organism are measured simultaneously in response to a physiological stimulus, we have identified protein-encoding genes induced by TNF through the type 1 receptor in cortical neurons, and a separate cohort of protein-encoding gene induced through the type 2 receptor. We are pursuing, and have obtained initial experimental support for, the hypothesis that at least one novel gene induced via type 1 TNF receptor elevation is deleterious to neuronal survival. We are exploring the neuroprotective effects of a group of proteins whose genes are induced via the type 2 receptor in neurons of the cerebral cortex. We anticipate that this work may be substantially relevant to the development of pharmacological agents to ameliorate inflammation-associated chronic neurodegenerative processes affecting cognition in the elderly.